The prevalence of obesity increased dramatically in the last 20 years and has rapidly become the most important health problem in the United States. Clinical and epidemiological studies suggest that obesity may cause cardiovascular and renal injury by many mechanisms in addition to hypertension and diabetes. The mechanisms of obesity-induced renal injury, especially the early changes that occur prior to development of diabetes, are poorly understood but may involve a combination of hemodynamic and metabolic abnormalities and intrarenal lipid accumulation. We propose that obesity-induced renal lipid accumulation causes mitochondrial dysfunction and endoplasmic reticulum (ER) stress which, in turn, lead to renal injury by a process known as "lipotoxicity". We will test the hypotheses that the increased leptin, which accompanies obesity, protects against renal lipid accumulation and injury. We will also determine whether Ang II, which also increases during obesity, promotes these changes. The following mouse models will be used to test our hypotheses in vivo: a mouse model of diet induced obesity (DIO) that mimics many of the metabolic and hemodynamic changes in human obesity, a genetically obese leptin-deficient mouse, and a genetically obese mouse with high levels of leptin. We will determine whether leptin protects against renal lipid accumulation and injury by stimulating fatty acid oxidation in the mitochondria. The role of Ang II in inducing mitochondrial dysfunction and ER stress by increasing renal lipid accumulation will be determined by blocking the Ang II type I receptor (AT1R) in DIO mice. Renal lipids will be measured quantitatively and the sites of lipid accumulation will be assessed histologically. Renal injury will be measured histologically based on the presence of cellular proliferation in glomeruli, thickened basement membranes, and increased collagen deposition, and functionally based on glomerular filtration rates and proteinuria. Telemetry will be used to continuously monitor mean arterial pressure and heart rate. Central to these studies will be the analysis of mitochondrial function, energy production, and the ER stress factors. This integrative approach combines chronic physiological experiments with biochemical and histological analyses that will provide us with novel insights into the mechanisms of obesity-induced renal injury. [unreadable] [unreadable] [unreadable] [unreadable]